The prefrontal cortex (PFC) plays a critical role in multiple cognitive processes. Dysfunction in the PFC has been implicated in a wide range of disorders including Alzheimer's disease, post-traumatic stress disorder, schizophrenia, and attention deficit hyperactivity disorder. Recent research has begun to focus on understanding how the PFC operates within functionally defined networks of brain structures. In particular, the PFC and medial temporal lobe areas such as the hippocampus may work together during the formation and retrieval of memory. This project will use trace fear conditioning (TFC) in laboratory rats as a model to understand the relative contributions of the PFC and hippocampus to the formation of new long-term memories. TFC differs from standard fear conditioning in that a small temporal gap, or "trace interval", is inserted between an auditory signal and an aversive outcome such as foot shock. Numerous studies have shown that normal learning in trace conditioning requires both the PFC and hippocampus, but the specific contributions of each structure as well as the principles by which they interact are currently not known. We will quantify the activity of intracellular signaling pathways known to be important for neural plasticity and learning within the PFC, hippocampus and amygdala in response to TFC training and determine how neural activity in one structure within this network affects responses in those connected to it. We will also determine the degree to which de novo protein synthesis within each brain area is required for the consolidation of a new TFC memory. This work represents the first systematic investigation of the molecular events required for memory formation in this network and one of very few studies to address the functional interactions between the PFC and hippocampus. PUBLIC HEALTH RELEVANCE: The prefrontal cortex (PFC) plays a critical role in multiple cognitive processes, and dysfunction in the PFC has been implicated in a wide range of disorders including Alzheimer's disease, post-traumatic stress disorder, schizophrenia, and attention deficit hyperactivity disorder. This study will provide important new data about how the PFC interacts with medial temporal lobe structures and about how molecular events in PFC neurons contribute to normal cognition.